A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

Abstract

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2-/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age.

Figure 1

(A-F) Families with CHEK2 I157T mutation. (G) The family with CHEK2 IVS2+1G>A mutation. (H) The family with CHEK2 1100delC mutation. Black symbols designate persons affected with cancer. The age of cancer onset is given after a disease symbol or above an arrow indicating a proband. ET: essential thrombocythemia; ALL: acute lymphoblastic leukemia; Br: breast cancer; St: stomach cancer; Pr: prostate cancer; Ki: kidney cancer; n.t.: not tested. The presence of a mutation is designated +, absence −.